RESUMEN
Purpose: To investigate the renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury (CI-AKI) in mice with type 1 diabetic mellitus(DM) using diffusion tensor imaging(DTI).Methods: Mice with DM were divided into two groups. In the diabetic + contrast medium(DCA) group, the changes of the mice kidneys were monitored at 1, 24, 48, and 72 h after the injection of iodixanol(4gI/kg). The mice in the diabetic + contrast medium + quercetin(DCA + QE) group were orally given different concentrations of quercetin for seven days before injection of iodixanol. In vitro experiments, renal tubular epithelial (HK-2) cells exposed to high glucose conditions were treated with various quercetin concentrations before treatment with iodixanol(250â mgI/mL).Results: DTI-derived mean diffusivity(MD) and fractional anisotropy(FA) values can be used to evaluate CI-AKI effectively. Quercetin significantly increased the expression of Sirt 1 and reduced oxidative stress by increasing Nrf 2/HO-1/SOD1. The antiapoptotic effect of quercetin on CI-AKI was revealed by decreasing proteins level and by reducing the number of apoptosis-positive cells. In addition, flow cytometry indicated quercetin-mediated inhibition of M1 macrophage polarization in the CI-AKI.Conclusions: DTI will be an effective noninvasive tool in diagnosing CI-AKI. Quercetin attenuates CI-AKI on the basis of DM through anti-oxidative stress, apoptosis, and inflammation.
Asunto(s)
Lesión Renal Aguda , Medios de Contraste , Diabetes Mellitus Tipo 1 , Imagen de Difusión Tensora , Quercetina , Animales , Quercetina/farmacología , Quercetina/uso terapéutico , Ratones , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/diagnóstico por imagen , Medios de Contraste/efectos adversos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Masculino , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Riñón/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ácidos TriyodobenzoicosRESUMEN
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be renoprotective in ischemia-reperfusion (I/R) injury, with several proposed mechanisms, though additional mechanisms likely exist. This study investigated the impact of luseogliflozin on kidney fibrosis at 48 h and 1 week post I/R injury in C57BL/6 mice. Luseogliflozin attenuated kidney dysfunction and the acute tubular necrosis score on day 2 post I/R injury, and subsequent fibrosis at 1 week, as determined by Sirius red staining. Metabolomics enrichment analysis of I/R-injured kidneys revealed suppression of the glycolytic system and activation of mitochondrial function under treatment with luseogliflozin. Western blotting showed increased nutrient deprivation signaling with elevated phosphorylated AMP-activated protein kinase and Sirtuin-3 in luseogliflozin-treated kidneys. Luseogliflozin-treated kidneys displayed increased protein levels of carnitine palmitoyl transferase 1α and decreased triglyceride deposition, as determined by oil red O staining, suggesting activated fatty acid oxidation. Luseogliflozin prevented the I/R injury-induced reduction in nuclear factor erythroid 2-related factor 2 activity. Western blotting revealed increased glutathione peroxidase 4 and decreased transferrin receptor protein 1 expression. Immunostaining showed reduced 4-hydroxynonenal and malondialdehyde levels, especially in renal tubules, indicating suppressed ferroptosis. Luseogliflozin may protect the kidney from I/R injury by inhibiting ferroptosis through oxidative stress reduction.
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Lesión Renal Aguda , Ferroptosis , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Ferroptosis/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Masculino , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Sorbitol/análogos & derivados , Sorbitol/farmacología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Estrés Oxidativo/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Transportador 2 de Sodio-GlucosaRESUMEN
The potential threat of cadmium (Cd)-induced acute kidney injury (AKI) is increasing. In this study, our primary goal was to investigate the individual roles played by mTOR complexes, specifically mTORC1 and mTORC2, in Cd-induced apoptosis in mouse kidney cells. We constructed a mouse model with specific deletion of Raptor/Rictor renal cells. Inhibitors and activators of mTORC1 or mTORC2 were also applied. The effects of protein kinase B (AKT) activation and autophagy were studied. Both mTORC1 and mTORC2 were found to mediate the antiapoptotic mechanism of renal cells by regulating the AKT activity. Inhibition of mTORC1 or mTORC2 exacerbated Cd-induced kidney cell apoptosis, suggesting that both proteins exert antiapoptotic effects under Cd exposure. We further found that the AKT activation plays a key role in mTORC1/TORC2-mediated antiapoptosis, protecting Cd-exposed kidney cells from apoptosis. We also found that mTOR activators inhibited excessive autophagy, alleviated apoptosis, and promoted cell survival. These findings provide new insights into the regulatory mechanisms of mTOR in renal diseases and provide a theoretical basis for the development of novel therapeutic strategies to treat renal injury.
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Lesión Renal Aguda , Apoptosis , Cadmio , Células Epiteliales , Túbulos Renales , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Proteínas Proto-Oncogénicas c-akt , Animales , Cadmio/toxicidad , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Apoptosis/efectos de los fármacos , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Lesión Renal Aguda/tratamiento farmacológico , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Túbulos Renales/efectos de los fármacos , Túbulos Renales/citología , Túbulos Renales/metabolismo , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Autofagia/efectos de los fármacos , Línea Celular , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which is associated with high incidence and mortality. AST-120 is an oral carbonaceous adsorbent that can alleviate kidney damage. This study aimed to explore the effects of AST-120 on renal IRI and the molecular mechanism. METHODS: A renal IRI mouse model was established and administrated AST-120, and differentially expressed genes were screened using RNA sequencing. Renal function and pathology were analyzed in mice. Hypoxia/reoxygenation (H/R) cell model was generated, and glycolysis was evaluated by detecting lactate levels and Seahorse analysis. Histone lactylation was analyzed by western blotting, and its relationship with hexokinase 2 (HK2) was assessed using chromatin immunoprecipitation. RESULTS: The results showed that HK2 expression was increased after IRI, and AST-120 decreased HK2 expression. Knockout of HK2 attenuated renal IRI and inhibits glycolysis. AST-120 inhibited renal IRI in the presence of HK2 rather than HK2 absence. In proximal tubular cells, knockdown of HK2 suppressed glycolysis and H3K18 lactylation caused by H/R. H3K18 lactylation was enriched in HK2 promoter and upregulated HK2 levels. Rescue experiments revealed that lactate reversed IRI that suppressed by HK2 knockdown. CONCLUSIONS: In conclusion, AST-120 alleviates renal IRI via suppressing HK2-mediated glycolysis, which suppresses H3K18 lactylation and further reduces HK2 levels. This study proposes a novel mechanism by which AST-120 alleviates IRI.
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Carbono , Modelos Animales de Enfermedad , Glucólisis , Hexoquinasa , Óxidos , Daño por Reperfusión , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Animales , Hexoquinasa/metabolismo , Hexoquinasa/genética , Glucólisis/efectos de los fármacos , Ratones , Masculino , Óxidos/farmacología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Ratones Endogámicos C57BL , Histonas/metabolismo , Humanos , Línea CelularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ischemia-reperfusion (IR) injury can result in acute renal failure. Oxidative stress is a major factor in IR-induced cell death in the kidneys. According to traditional Chinese medicine, earthworms (Pheretima aspergillum) can be used to treat various kidney diseases. AIM OF THE STUDY: The present study was designed to understand the protective effects of the water extract of earthworms (WEE) against oxidative stress on the kidneys and the crucial molecular events associated with its nephroprotective activity. MATERIALS AND METHODS: Cytotoxicity caused by H2O2 in HEK293, HK2, and primary mouse renal tubular epithelial cells (TECs) was used to investigate the effect of WEE on oxidative stress-induced renal injury in vitro. IR-induced kidney injury was established using rats as an in vivo model. The WEE-mediated protection of the kidneys against oxidative stress was compared with that of glutathione, a common antioxidant used as a positive control. RESULTS: In HEK293 cells, HK2 cells, and primary mouse TECs, WEE relieved H2O2-induced mitochondrial damage, apoptosis, and ferroptosis. In kidney cells, WEE increased the expression of Sirt1, boosted LKB1 and AMPK phosphorylation, and upregulated nuclear Nrf2. Suppression of Sirt1 and LKB1 knock down abrogated WEE-induced protection against H2O2. WEE ameliorated IR-induced kidney injury and intrarenal inflammation in rats. In rat kidneys, WEE mitigated mitochondrial damage and suppressed IR-induced apoptosis and ferroptosis. Mechanistically, WEE increased Sirt1 expression, enhanced the phosphorylation of LKB1 and AMPK, and increased intranuclear Nrf2 levels in IR kidneys. IR treatment resulted in considerable increase in renal MDA levels and a prominent decrease in antioxidative enzyme activity. These lesions were significantly alleviated by WEE. CONCLUSIONS: WEE mitigated H2O2-induced cytotoxicity in kidney cells in vitro and improved IR-induced kidney damage in rats. Mechanistically, WEE potentiated the Sirt1/Nrf2 axis and relieved mitochondrial damage in the kidney cells. These events inhibited the apoptosis and ferroptosis induced by oxidative stress. Our findings support the potential application of WEE for the clinical treatment of kidney diseases caused by intrarenal oxidative stress.
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Mitocondrias , Factor 2 Relacionado con NF-E2 , Oligoquetos , Estrés Oxidativo , Ratas Sprague-Dawley , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Células HEK293 , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino , Ratas , Peróxido de Hidrógeno/toxicidad , Apoptosis/efectos de los fármacos , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Agua/química , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Antioxidantes/farmacologíaRESUMEN
Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the renal function and has high morbidity and mortality worldwide, yet there is no satisfactory means of prevention and treatment at present. Dioscin, a natural steroidal saponin, has been found to have antioxidant, anti-inflammatory and anti-apoptotic effects. In this experiment, we pretreated cisplatin-induced AKI rats with dioscin and found that dioscin significantly enhanced renal function and reduced renal pathological injury in AKI rats. We also found that dioscin improved renal antioxidant capacity by suppressing the accumulation of oxides such as ROS, MDA and H2O2, and increasing the levels of antioxidant enzymes SOD and CAT. In addition, dioscin down-regulated the expression of inflammation-related proteins (IL-1ß, TNF-α, NF-κB) and necroptosis-critical proteins RIP1/RIP3, whereas up-regulated Caspase-8 protein levels in the kidney of AKI rats. Mechanistically, dioscin promoted the nuclear transcription of Nrf2 and activated Nrf2/HO-1 signaling axis to play a positive role in the kidney of AKI rats, while the reno-protective effect of dioscin was significantly attenuated after inhibiting Nrf2. In conclusion, our data indicate that dioscin decreases cisplatin-induced renal oxidative stress and thwarts necroptosis induced inflammation via regulating the Nrf2/HO-1pathway. Our study provides more data and theoretical support for the study of natural drugs to improve AKI.
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Lesión Renal Aguda , Antiinflamatorios , Cisplatino , Diosgenina , Riñón , Necroptosis , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Diosgenina/análogos & derivados , Diosgenina/farmacología , Diosgenina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Masculino , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Cisplatino/efectos adversos , Necroptosis/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Ratas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Inflamación/tratamiento farmacológico , Humanos , Modelos Animales de EnfermedadRESUMEN
AIMS: Losartan potassium-laden pegylated nanocubic vesicles (LP-NCVs-PEG) have an intriguing kidney-targeted nanoplatform for acute renal injury via blocking apoptosis and activating wnt/ß-catenin pathway. MAIN METHODS: Utilizing a thin-film hydration methodology established on 42 full factorial design to produce LP loaded nanocubic formulations (LP-NCVs) which composed mainly from L-α-phosphatidylcholine and poloxamer. The optimization process was designed to select the formulation with maximum entrapment efficiency (EE %), maximum in-vitro drug release (Q8h), and minimum vesicle size (VS). The optimum formulation was then pegylated to obtain LP-NCVs-PEG formulation that shields NCVs from the harsh ecosystem of the stomach, improves their oral drug delivery performance and targets the proximal renal tubules with no systemic toxicity. Male albino rats were injected with Cisplatin (6 mg/kg, i.p.) alone or with LP-formulations (5 mg/kg/day). Kidney injury markers, inflammatory markers, apoptotic markers. Besides renal tissue expression of Wnt, ß-Catenin, GSK-3ß, renal RNA gene expression of TCF-4, LEF-1 and histopathology were also analyzed to display pharmacological study. KEY FINDINGS: The pharmacokinetics studies demonstrated that LP-NCVs-PEG boosted LP bioavailability approximately 3.61 times compared to LP oral solution. Besides LP-NCVs-PEG may have an intriguing kidney-targeted nanoplatform for acute renal injury via decreased renal toxicity markers, renal expression of LEF-1, GSK3-ß, caspase, TNF-α, NF-κB and TUNEL expression. Alternatively, increased renal tissue level of Bcl-2, wnt, ß-catenin and TCF-4. SIGNIFICANCE: LP-NCVs-PEG improved LP pharmacokinetics targeting the kidney and improved injury by activating wnt/ß-catenin/TCF-4 pathway, blocking apoptosis, inflammation and renal toxicity markers suggesting it might be successful nephroprotective adjuvant therapy.
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Lesión Renal Aguda , Apoptosis , Cisplatino , Losartán , Polietilenglicoles , Vía de Señalización Wnt , Animales , Masculino , Ratas , Apoptosis/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Polietilenglicoles/química , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Losartán/farmacología , beta Catenina/metabolismo , Nanopartículas/química , Factor de Transcripción 4/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Antineoplásicos/farmacología , Ratas Wistar , Liberación de FármacosRESUMEN
Cardio-Renal-Metabolic (CaReMe) diseases, in the form of heart failure, chronic kidney disease and diabetes mellitus, justify prescription of multiple prognostically beneficial medications, specifically renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 inhibitors. Use of these medications is complicated by association with adverse effects, particularly acute kidney injury and hyperkalaemia. Balancing risk and benefit is a common dilemma in acute medicine, with increasingly frequent and complex treatment decisions. Physicians should contemplate adjustments to medications within the context of not just acute illness but also long-term benefit. In the setting of hyperkalaemia, potassium-binding medications can be utilised. At hospital discharge optimisation of therapy can be achieved through clear safety netting advice, scheduled biochemical follow-up, and planned clinical review.
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Lesión Renal Aguda , Hiperpotasemia , Humanos , Hiperpotasemia/tratamiento farmacológico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/terapia , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/terapia , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
RATIONALE: Hashimoto thyroiditis (HT), a common cause of hypothyroidism, has shown an increasing incidence in recent years, particularly among women. In addition to the common complications such as lipid metabolism disorders, patients with HT may also experience some serious complications, acute kidney injury and severe muscle damage for instance. This article explored the effectiveness of levothyroxine sodium tablets (L-T4) replacement therapy in severe complications of hypothyroidism, including treatment dosage, duration of complication recovery, and whether additional treatment is needed. PATIENT CONCERNS, DIAGNOSES, AND INTERVENTIONS: We described a case of a 52-year-old woman with HT who exhibited kidney injury, muscle injury, and lipid metabolism disorders. The increased levels of serum creatinine, creatine kinase, cholesterol, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and the decreased levels of estimated glomerular filtration rate were obviously observed. This patient was started on L-T4 (75 and 100 µg, alternate). OUTCOMES AND LESSONS: Following a two-month treatment, the serum creatine kinase level decreased to within normal range. The estimated glomerular filtration rate level was restored, and the serum creatinine level was down-regulated, although slightly higher than the normal range. L-T4 partially reversed HT-induced the disorders of muscle, renal function, and lipid profile of this patient and remarkably alleviated her HT-related symptoms.
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Lesión Renal Aguda , Enfermedad de Hashimoto , Tiroxina , Humanos , Femenino , Persona de Mediana Edad , Enfermedad de Hashimoto/complicaciones , Enfermedad de Hashimoto/tratamiento farmacológico , Tiroxina/uso terapéutico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/tratamiento farmacológico , Trastornos del Metabolismo de los Lípidos/tratamiento farmacológico , Trastornos del Metabolismo de los Lípidos/complicaciones , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/etiología , ComprimidosRESUMEN
Epigallocatechin gallate (EGCG)-based nanosystems have garnered significant attention for their ability to alleviate inflammation due to their excellent anti-inflammatory properties and enhanced drug delivery capabilities. However, the degradation of EGCG in strongly acidic environments poses a challenge for potential administration, particularly in oral formulations, where gastric resistance is essential. In this study, we develop a "disintegration and reorganization" strategy to create acid-resistant antioxidant nanoparticles (EGA NPs) based on EGCG and 5-aminosalicylic acid (5-ASA) for mitigating inflammation in colitis and acute kidney injury. At acidic pH, the ester bond in EGCG breaks down, producing two building blocks. These, together with 5-ASA and formaldehyde, form oligomers through a combination of phenol-aldehyde condensation and the Mannich reaction. The resulting oligomers self-assemble into EGA NPs, which exhibit significant stability under both acidic and neutral pH conditions. This stability makes them suitable for oral administration, allowing them to withstand harsh gastric conditions, as well as for intravenous injection. Importantly, these oligomers retain the antioxidant and anti-inflammatory properties of EGCG, effectively scavenging reactive oxygen species and reducing intracellular oxidative stress. Additionally, EGA shows potential as a drug carrier, efficiently loading the anti-inflammatory agent curcumin (Cur) to form Cur@EGA NPs. In vivo studies demonstrate the efficacy of Cur@EGA and EGA in alleviating acute colitis and kidney injury following oral and intravenous administration, respectively. These nanoparticulate formulations exhibit superior inflammation reduction compared to free Cur in vivo. Overall, our findings introduce a novel acid-resistant nanoplatform based on EGCG for the treatment of acute inflammation.
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Lesión Renal Aguda , Antioxidantes , Catequina , Nanopartículas , Catequina/análogos & derivados , Catequina/química , Catequina/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacología , Ratones , Nanopartículas/química , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Colitis/tratamiento farmacológico , Colitis/patología , Inflamación/tratamiento farmacológico , Concentración de Iones de Hidrógeno , Mesalamina/química , Mesalamina/farmacología , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Masculino , Portadores de Fármacos/química , HumanosRESUMEN
Heavy metals are environmental pollutants that can harm animals and humans even at low concentrations. Cadmium (Cd) is known for its serious health effects on different organs and its toxicity is associated with oxidative stress (OS) and inflammation. Farnesol (FAR), a sesquiterpene alcohol found in many vegetables and fruits, possesses promising anti-inflammatory and antioxidant activities. This study evaluated the effect of FAR on Cd-induced kidney injury, pinpointing its effect of the redox status, inflammation, fibrosis and necroptosis. Rats in this study received FAR for 14 days and Cd on day 7. Elevated serum creatinine, urea and uric acid, and several kidney histopathological alterations were observed in Cd-administered rats. Cd increased MDA, decreased antioxidants, downregulated PPARγ and upregulated NF-κB p65, IL-6, TNF-α, and IL-1ß. Necroptosis mediators (RIP1, RIP3, MLKL, and caspase-8) and α-SMA were upregulated, and collagen deposition was increased in Cd-administered rats. FAR ameliorated kidney injury markers and tissue damage, attenuated OS, suppressed NF-κB and inflammatory mediators, and enhanced antioxidants. In addition, FAR suppressed RIP1, RIP3, MLKL, caspase-8, and α-SMA, and enhanced kidney cytoglobin and PPARγ. In conclusion, FAR protects against Cd nephrotoxicity by suppressing OS, inflammatory response and necroptosis, effects associated with enhanced antioxidants, cytoglobin, and PPARγ.
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Cadmio , Citoglobina , Farnesol , Inflamación , Necroptosis , Estrés Oxidativo , PPAR gamma , Regulación hacia Arriba , Animales , Estrés Oxidativo/efectos de los fármacos , Cadmio/toxicidad , Inflamación/patología , Inflamación/metabolismo , Ratas , PPAR gamma/metabolismo , Necroptosis/efectos de los fármacos , Masculino , Regulación hacia Arriba/efectos de los fármacos , Citoglobina/metabolismo , Farnesol/farmacología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Ratas Wistar , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Antioxidantes/farmacología , Antioxidantes/metabolismoAsunto(s)
Lesión Renal Aguda , Antieméticos , Cisplatino , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/tratamiento farmacológico , Cisplatino/efectos adversos , Humanos , Antieméticos/uso terapéutico , Antieméticos/administración & dosificación , Antineoplásicos/efectos adversos , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Vómitos/prevención & controlRESUMEN
INTRODUCTION: Acute kidney injury (AKI) is a serious pathology that progress with dysfunction of regulating blood pressure and fluid balance, concentrating urine due to decrement of aquaporin-1 (AQP) levels during the inflammation process. Irbesartan (IRN), angiotensin receptor blocker, is widely used in the treatment of hypertension, which also has anti-inflammatory, antioxidant and anti-apoptotic properties. The aim of this study is to investigate the protective effects of IRN in lipopolysaccharide (LPS)-induced kidney injury. MATERIAL AND METHODS: Twenty-four rats divided into three groups as control, LPS and LPS+IRN group. After 6h of LPS administration, rats were sacrificed. Blood samples and half of the kidney tissues were collected for biochemical analysis and remaining tissues were taken for histopathological and immunohistochemical analysis. RESULTS: In the LPS group, glomerular congestion and shrinkage, degeneration of distal tubules, mononuclear cell infiltration, cellular debris and intense proteinous accumulation in the tubules, increased expressions of Cas-3, nuclear factor kappa beta-p65 (NF-kB p65), levels of creatinin, TOS, OSI and decreased levels of TAS, AQP-1 were found significantly. IRN treatment reversed all these parameters. IRN's restorated AQP-1 levels by its anti-inflammatory, antioxidant and anti-apoptotic effects due to inhibiting NF-kB expression. CONCLUSION: This study suggests that IRN can be used in conditions affecting the kidneys such as AKI. Further studies needed for detailed molecular investigation of IRN at different doses and durations.
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Lesión Renal Aguda , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Acuaporina 1 , Modelos Animales de Enfermedad , Irbesartán , FN-kappa B , Animales , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Irbesartán/farmacología , Irbesartán/uso terapéutico , Ratas , FN-kappa B/metabolismo , Masculino , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Ratas WistarRESUMEN
Chlorpyrifos (CPF) is a highly toxic commonly used pesticide and can seriously harm human health. This study assessed the potential of galangin (GAL), an antioxidant flavonoid, to attenuate oxidative stress, inflammation and kidney injury caused by CPF, emphasizing the role of farnesoid-x-receptor (FXR) and Nrf2. Rats were supplemented with CPF and GAL for 28 days. CPF increased serum creatinine, urea and Kim-1, provoked several tissue alterations, and increased kidney ROS, malondialdehyde (MDA), NF-κB p65, TNF-α, iNOS, and caspase-3. GAL effectively ameliorated serum kidney injury markers, ROS, MDA, and TNF-α, suppressed NF-κB p65, iNOS, and caspase-3, and enhanced antioxidants. GAL suppressed Keap1 and upregulated FXR, Nrf2, HO-1 and NQO-1 in CPF-administered rats. GAL exhibited binding affinity with Keap1, FXR, caspase-3, iNOS, HO-1, and NF-κB. In conclusion, GAL is effective in preventing CPF nephrotoxicity by attenuating oxidative stress and inflammation. This protection is linked to upregulation of antioxidants, Nrf2/HO-1 signaling and FXR.
Asunto(s)
Cloropirifos , Flavonoides , Riñón , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Receptores Citoplasmáticos y Nucleares , Regulación hacia Arriba , Animales , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Cloropirifos/toxicidad , Masculino , Flavonoides/farmacología , Flavonoides/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Receptores Citoplasmáticos y Nucleares/metabolismo , Ratas , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Insecticidas/toxicidad , Antioxidantes/farmacología , Ratas Wistar , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & controlRESUMEN
Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs (G3-G10) and 40 simplifiers (G11-G50) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava. Among these compounds, (d)-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo, and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that (d)-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. (d)-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.
Asunto(s)
Lesión Renal Aguda , Antineoplásicos , Cisplatino , Psidium , Cisplatino/farmacología , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Ratones , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Psidium/química , Terpenos/farmacología , Terpenos/síntesis química , Terpenos/química , Masculino , Relación Estructura-ActividadRESUMEN
A woman in her 40s with no medical history presented on hospital day #0 with 3 days of epigastric pain, nausea, vomiting and bloody diarrhoea. Initial blood work demonstrated acute kidney injury with metabolic acidosis with an elevated anion gap, thrombocytopenia, an elevated lactate dehydrogenase, and an undetectable haptoglobin. She was quickly diagnosed with haemolytic uraemic syndrome from Shiga toxin-producing O157:H7 Escherichia coli Her microangiopathic haemolytic anaemia and renal failure progressively worsened and only improved after the initiation of eculizumab, a monoclonal antibody directed against complement component C5. We report a case of Shiga toxin-producing E. coli-haemolytic uraemia syndrome with a complement-mediated component.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndrome Hemolítico-Urémico , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Adulto , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/complicaciones , Escherichia coli O157 , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Inactivadores del Complemento/uso terapéuticoRESUMEN
Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response via the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1ß and NLRP3) via blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.
Asunto(s)
Lesión Renal Aguda , Ácido Quenodesoxicólico , Modelos Animales de Enfermedad , Mitocondrias , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Ratas Sprague-Dawley , Sepsis , Transducción de Señal , Animales , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacología , Ácido Quenodesoxicólico/uso terapéutico , FN-kappa B/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Transducción de Señal/efectos de los fármacos , Ratas , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Acute kidney injury (AKI), predominantly associated with the excess production of endogenous ROS, is a serious renal dysfunction syndrome. Ferroptosis characterized by iron-dependent regulated cell death has significant involvement in AKI pathogenesis. As symptomatic treatment of AKI remains clinically limited, a new class of effective therapies has emerged, which is referred to as nanozyme. In our research, a natural mesoporous poly(tannic acid) nanosphere (referred to as PTA) was developed that can successfully mimic the activity of superoxide dismutase (SOD) by Mussel-inspired interface deposition strategy, for effective ROS scavenging and thus inhibition of ferroptosis to attenuate AKI. As anticipated, PTA mitigated oxidative stress and inhibited ferroptosis, as opposed to other modes of cell death such as pyroptosis or necrosis. Furthermore, PTA exhibited favorable biocompatibility and safeguarded the kidney against ferroptosis by enhancing the expression of SLC7a11/glutathione peroxidase 4(GPX4) and Nrf2/HO-1, while reducing the levels of ACSL4 protein in the ischemia and reperfusion injury (IRI)-induced AKI model. Moreover, PTA effectively suppressed aberrant expression of inflammatory factors. Overall, this study introduced antioxidative nanozymes in the form of mesoporous polyphenol nanospheres, showcasing exceptional therapeutic efficacy in addressing ROS-related diseases. This novel approach holds promise for clinical AKI treatment and broadens the scope of biomedical applications for nanozymes.
Asunto(s)
Lesión Renal Aguda , Ferroptosis , Nanosferas , Especies Reactivas de Oxígeno , Taninos , Ferroptosis/efectos de los fármacos , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Nanosferas/química , Especies Reactivas de Oxígeno/metabolismo , Ratones , Taninos/farmacología , Taninos/química , Taninos/uso terapéutico , Masculino , Estrés Oxidativo/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Porosidad , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , PolifenolesRESUMEN
Introduction: Rhabdomyolysis, as an acute stage of myopathy, causes kidney damage. It is known that this pathology is caused by the accumulation of muscle breakdown products and is associated with oxidative stress. Therefore, the present study evaluated the effect of intraperitoneal administration (dose 1 mg/kg) of water-soluble C60 fullerenes, as powerful antioxidants, on the development of rat kidney damage due to rhabdomyolysis caused by mechanical trauma of the muscle soleus of different severity (crush syndrome lasting 1 min under a pressure of 2.5, 3.5, and 4.5 kg/cm2, respectively). Methods: Using tensometry, biochemical and histopathological analyses, the biomechanical parameters of muscle soleus contraction (contraction force and integrated muscle power), biochemical indicators of rat blood (concentrations of creatinine, creatine phosphokinase, urea and hydrogen peroxide, catalase and superoxide dismutase activity), glomerular filtration rate and fractional sodium excretion value, as well as pathohistological and morphometric features of muscle and kidney damages in rats on days 1, 3, 6 and 9 after the initiation of the injury were studied. Results: Positive changes in biomechanical and biochemical parameters were found during the experiment by about 27-30 ± 2%, as well as a decrease in pathohistological and morphometric features of muscle and kidney damages in rats treated with water-soluble C60 fullerenes. Conclusion: These findings indicate the potential application of water-soluble C60 fullerenes in the treatment of pathological conditions of the muscular system caused by rhabdomyolysis and the associated oxidative stress.